This proposal focuses on pathogenetic and etiologic studies of autoimmune diseases of man primarily systemic lupus erthematosus (SLE), mixed connective tissue disease with features of SLE, scleroderma and myositis, pemphigus vulgaris and bullous pemphigoid. Several approaches will be employed. 1.) Characterization of circulating autoantibodies as to immunoglobulin class, IgG subgroup and in vitro complement fixation by indirect immunofluorescence employing fluorescent antisera specific for IgG, IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgD and IgE, C1q, C3 and C4. Specificity of antisera will be confirmed both by specific blocking experiments with purified myeloma proteins and with hemagglutination by coupling purified myeloma proteins to red blood cells. Sera containing a mixture of autoantibodies will be characterized for specific antibody populations using hemagglutination or precipitin reactions. Antibodies directed toward native DNA (DS-DNA), heat-denatured DNA (HSS-DNA), Sm antigen, extractable nuclear antigen (ENA) and whole ribosomes (Rb) or RNA will be isolated using quantitative precipitation or immunosorbents and isolated antibodies will be characterized by indirect immunofluorescence, single radial diffusion, or immunoassay as to class and subgroup. Particular emphasis will be placed on antibodies to DS- DNA and ENA, as these appear to correlate well with course and prognosis in SLE, and in mixed connective tissue disease syndrome high titers of antibodies to ENA also predominate and are associated with excellent fluorescent studies of immunosuppression. 2.) Correlation with direct fluorescent studies of biopsy and postmortem tissues and class and subgroup of circulating autoantibodies will be made. Deposits will be eluted from tissues and characterized as to specificity. 3.) Simultaneous evaluation of all biopsy materials and buffy coats for viral particles by electron microscopy. Attempted propagation of selected biopsy tissues or peripheral leukocytes containing such particles in tissues culture will be carried out. Isolation of particles will be attempted and interactions with circulating and deposited autoantibodies studied.